Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production

Toyonaga, Jiro; Tsuruya, Kazuhiko; Ikeda, Hirofumi; Noguchi, Hideko; Yotsueda, Hideki; Fujisaki, Kiichiro; Hirakawa, Makoto; Taniguchi, Masatomo; Masutani, Kohsuke; Iida, Mitsuo

doi:10.1093/ndt/gfq750

Cited by 85 publications

(62 citation statements)

References 57 publications

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“…The gene expression levels of 8-OHdG and Nox4 in the kidney of db/db mice were relatively low at 6 weeks of age, but their expression markedly increased with increasing albuminuria and mesangial expansion at 9 weeks of age. Consistent with previous studies [25,26,27], these results indicate that oxidative stress is involved in the pathogenesis of diabetic nephropathy. Telmisartan suppressed albuminuria and mesangial expansion in db/db mice without affecting blood glucose levels or blood pressure.…”

Section: Discussionsupporting

confidence: 93%

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in db/db Mice

Sato-Horiguchi¹,

Ogawa²,

Wada³

et al. 2013

Nephron Exp Nephrol

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Background/Aims: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. Methods: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. Results: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-β) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. Conclusions: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress.

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Section: Discussionsupporting

confidence: 93%

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in db/db Mice

Sato-Horiguchi¹,

Ogawa²,

Wada³

et al. 2013

Nephron Exp Nephrol

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“…H 2 O 2 (500 μM) treatment also increased HO-1 protein levels. Several similar studies have been described in other cell types [50,51,52]. However, several possible mechanisms most likely exist for HG-induced ROS generation, which mediated the up-regulation of HO-1 expression.…”

Section: Discussionsupporting

confidence: 56%

High Glucose Promotes Tumor Invasion and Increases Metastasis-Associated Protein Expression in Human Lung Epithelial Cells by Upregulating Heme Oxygenase-1 via Reactive Oxygen Species or the TGF-β1/PI3K/Akt Signaling Pathway

Kang

Kong

et al. 2015

Cell Physiol Biochem

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Background: Growing evidence indicates that heme oxygenase-1 (HO-1) is up-regulated in malignancies and subsequently alters tumor aggressiveness and various cancer-related factors, such as high glucose (HG) levels. HO-1 expression can be induced when glucose concentrations are above 25 mM; however, the role of HO-1 in lung cancer patients with diabetes remains unknown. Therefore, in this study we investigated the promotion of tumor cell invasion and the expression of metastasis-associated proteins by inducing the up-regulation of HO-1 expression by HG treatment in A549 human lung epithelial cells. Methods: The expression of HO-1and metastasis-associated protein expression was explored by western blot analysis. HO-1 enzymatic activity, reactive oxygen species (ROS) production and TGF-β₁ production were examined by ELISA. Invasiveness was analyzed using a Transwell chamber. Results: HG treatment of A549 cells induced an increase in HO-1 expression, which was mediated by the HG-induced generation of reactive oxygen species (ROS) and transforming growth factor-β1 (TGF-β₁) in a concentration- and time-dependent manner. Following the increase in HO-1 expression, the enzymatic activity of HO-1 also increased in HG-treated cells. Pretreatment with N-acetyl-L-cysteine (NAC) or with phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors attenuated the HG-induced increase in HO-1 expression. HG treatment of A549 cells enhanced the invasion potential of these cells, as shown with a Transwell assay, and increased metastasis-associated protein expression. However, HO-1 siRNA transfection significantly decreased these capabilities. Conclusion: this study is the first to demonstrate that HG treatment of A549 human lung epithelial cells promotes tumor cell invasion and increases metastasis-associated protein expression by up-regulating HO-1 expression via ROS or the TGF-β₁/PI3K/Akt signaling pathway.

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“…Further clinical and experimental studies have demonstrated an increased level of inflammatory markers such as macrophage-chemoattractant protein 1 and transforming growth factor b1, osteopontin, interleukin 1 (IL1), and IL6 expression due to aldosterone excess (14,15,16,17,18). Especially, the excess of aldosterone in combination with an elevated salt intake results in renal inflammation, fibrosis, podocyte injury, and mesangial cell proliferation (19,20).…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Fourkiotis

Vonend²,

Diederich³

et al. 2013

European Journal of Endocrinology

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Objective: Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce. Design and methods: This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; nZ86); spironolactone (nZ65); and eplerenone (nZ18)). Results: GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications. Conclusions: Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

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Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production

Abstract: We conclude that hyperglycemia in diabetes, independent of plasma aldosterone concentration, induces podocyte injury through MR-mediated ROS production and leads to proteinuria. SPL inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.

Cited by 85 publications

References 57 publications

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in <b><i>db/db</i></b> Mice

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in <b><i>db/db</i></b> Mice

High Glucose Promotes Tumor Invasion and Increases Metastasis-Associated Protein Expression in Human Lung Epithelial Cells by Upregulating Heme Oxygenase-1 via Reactive Oxygen Species or the TGF-β1/PI3K/Akt Signaling Pathway

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

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